Obstructive sleep apnea and non-alcoholic Fatty liver disease: is the liver another target?

Mirrakhimov AE, Polotsky VY - Front Neurol (2012)

Bottom Line:
Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known.Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation.The mouse model provided insight in the pathogenesis of liver injury showing that (1) IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA) flux into the liver; (2) IH up-regulates lipid biosynthetic pathways in the liver; (3) IH induces oxidative stress in the liver; (4) IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis.

ABSTRACTObstructive sleep apnea (OSA) is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH). OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD). NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH), liver fibrosis, and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1) IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA) flux into the liver; (2) IH up-regulates lipid biosynthetic pathways in the liver; (3) IH induces oxidative stress in the liver; (4) IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done.

Figure 1: (A) A representative image of the liver without inflammation in the individual without OSA. Hematoxylin-eosin. X 100. Macrovesicular hepatic steatosis is evident, but inflammation is absent; (B) A representative image of the liver in the individual with OSA and severe nocturnal oxyhemoglobin desaturation. Hematoxylin-eosin.X 100. Macrovesicular hepatic steatosis is evident, lobular inflammation is present (arrows); (C) A representative image of the liver without pericellular fibrosis in the individual without OSA. Masson trichrome X 100; (D) A representative image of the liver in the individual with OSA and severe nocturnal oxyhemoglobin desaturation. Masson trichrome X 100. Prominent pericellular perisinusoidal fibrosis is present. Collagen depositions are stained in blue and have chicken-wire appearance. Reproduced with permission from Polotsky et al. (2009).

Mentions:
The gold standard of NAFLD diagnosis, staging, and prognosis is liver biopsy. The first case report of severe NASH with intralobular and periportal inflammation, hepatocyte ballooning, and pericellular fibrosis in a patient with obesity hypoventilation syndrome was published in 2002 (Saibara et al., 2002). Since that time a number of studies examining relationships between OSA and findings in liver biopsy have been conducted (Table 2). All of these studies are cross-sectional, because it is not feasible to obtain liver biopsy repeatedly due to ethical considerations. Studies, in which polysomnography (PSG) has not been performed could not be used for the reliable analysis of the OSA-NAFLD association and will not be further discussed. In the first PSG based study, Tanne et al. (2005) performed liver biopsy in a small subset of sleep clinic patients with elevated serum liver enzymes and found that subjects with severe OSA defined as the AHI > 50/h (n = 9), exhibited more severe liver steatosis, necrosis, and fibrosis than subjects with the AHI ≤ 50/h (n = 9). Other studies focused on the bariatric population taking an advantage of the availability of intra-operative liver biopsy. Kallwitz et al. (2007) performed a retrospective review of 101 patients who underwent gastric bypass surgery. Liver biopsy was performed only if the liver had abnormal appearance (enlargement, yellow discoloration, or nodularity). Both PSG and liver biopsy were performed in 85 patients. There was a trend toward a higher prevalence of OSA in patients with inflammation and fibrosis (11/15) compared with those with inflammation alone (22/48). There was no association between OSA and the degree of steatosis, presence of hepatitis, balloon degeneration, or fibrosis on liver biopsy. Similarly, Jouet et al. (2007) also reported the lack of association between OSA and histological markers of NASH. However, relationships between nocturnal hypoxemia and NASH had not been examined. Mishra et al. (2008) studied 101 bariatric patients with biopsy-proven NAFLD, all of whom had full PSG in a sleep laboratory. The lowest desaturation independently correlated with histological NASH. Both mean and lowest oxygen desaturation were independently associated with the presence of liver fibrosis, whereas there was no statistically significant relationships between the AHI and RDI (the respiratory disturbance index defined as a number of apneas, hypopneas, and respiratory effort related arousals per hour) and liver fibrosis. Polotsky et al. (2009) studied 90 consecutive bariatric patients, all of which underwent PSG, and reported the prevalence of OSA (the RDI > 5/h) of 81.1%. The analysis of liver biopsies (n = 20) showed that lobular inflammation, hepatocyte ballooning, the NAS, and liver fibrosis were associated with severe oxyhemoglobin desaturation (Figure 1), but not the RDI and this association was independent of BMI. Aron-Wisnewsky et al. (2012) performed continuous nocturnal pulse oximetry in 101 bariatric patients who underwent liver needle biopsy intra-operatively. Liver histology was compared in three tertiles of oxygen desaturation index (ODI), <6.7, 6.8–18.5, and >18.5 /h. The BMI was similar in all tertiles varying from 45.7 to 48.3 kg/m2, whereas patients with more severe OSA had higher prevalence of type 2 diabetes, dyslipidemia, and hypertension. There was a significant increase in liver steatosis, ballooning, lobular inflammation, NAS, and liver fibrosis with increased ODI. After the adjustment for type 2 diabetes, inflammation, age, and sex, the ODI remained independently associated with higher NAS and the severity of liver fibrosis. Notably, similarly to Polotsky et al. (2009), ALT and AST values were within the normal range in all patients, regardless of the severity of OSA and NASH. Thus, emerging evidence demonstrates that there is an association between the severity of hypoxic indexes in patients with OSA and the severity of NAFLD diagnosed by liver biopsy. The effect of CPAP treatment on NAFLD pathology has not been examined.

Figure 1: (A) A representative image of the liver without inflammation in the individual without OSA. Hematoxylin-eosin. X 100. Macrovesicular hepatic steatosis is evident, but inflammation is absent; (B) A representative image of the liver in the individual with OSA and severe nocturnal oxyhemoglobin desaturation. Hematoxylin-eosin.X 100. Macrovesicular hepatic steatosis is evident, lobular inflammation is present (arrows); (C) A representative image of the liver without pericellular fibrosis in the individual without OSA. Masson trichrome X 100; (D) A representative image of the liver in the individual with OSA and severe nocturnal oxyhemoglobin desaturation. Masson trichrome X 100. Prominent pericellular perisinusoidal fibrosis is present. Collagen depositions are stained in blue and have chicken-wire appearance. Reproduced with permission from Polotsky et al. (2009).

Mentions:
The gold standard of NAFLD diagnosis, staging, and prognosis is liver biopsy. The first case report of severe NASH with intralobular and periportal inflammation, hepatocyte ballooning, and pericellular fibrosis in a patient with obesity hypoventilation syndrome was published in 2002 (Saibara et al., 2002). Since that time a number of studies examining relationships between OSA and findings in liver biopsy have been conducted (Table 2). All of these studies are cross-sectional, because it is not feasible to obtain liver biopsy repeatedly due to ethical considerations. Studies, in which polysomnography (PSG) has not been performed could not be used for the reliable analysis of the OSA-NAFLD association and will not be further discussed. In the first PSG based study, Tanne et al. (2005) performed liver biopsy in a small subset of sleep clinic patients with elevated serum liver enzymes and found that subjects with severe OSA defined as the AHI > 50/h (n = 9), exhibited more severe liver steatosis, necrosis, and fibrosis than subjects with the AHI ≤ 50/h (n = 9). Other studies focused on the bariatric population taking an advantage of the availability of intra-operative liver biopsy. Kallwitz et al. (2007) performed a retrospective review of 101 patients who underwent gastric bypass surgery. Liver biopsy was performed only if the liver had abnormal appearance (enlargement, yellow discoloration, or nodularity). Both PSG and liver biopsy were performed in 85 patients. There was a trend toward a higher prevalence of OSA in patients with inflammation and fibrosis (11/15) compared with those with inflammation alone (22/48). There was no association between OSA and the degree of steatosis, presence of hepatitis, balloon degeneration, or fibrosis on liver biopsy. Similarly, Jouet et al. (2007) also reported the lack of association between OSA and histological markers of NASH. However, relationships between nocturnal hypoxemia and NASH had not been examined. Mishra et al. (2008) studied 101 bariatric patients with biopsy-proven NAFLD, all of whom had full PSG in a sleep laboratory. The lowest desaturation independently correlated with histological NASH. Both mean and lowest oxygen desaturation were independently associated with the presence of liver fibrosis, whereas there was no statistically significant relationships between the AHI and RDI (the respiratory disturbance index defined as a number of apneas, hypopneas, and respiratory effort related arousals per hour) and liver fibrosis. Polotsky et al. (2009) studied 90 consecutive bariatric patients, all of which underwent PSG, and reported the prevalence of OSA (the RDI > 5/h) of 81.1%. The analysis of liver biopsies (n = 20) showed that lobular inflammation, hepatocyte ballooning, the NAS, and liver fibrosis were associated with severe oxyhemoglobin desaturation (Figure 1), but not the RDI and this association was independent of BMI. Aron-Wisnewsky et al. (2012) performed continuous nocturnal pulse oximetry in 101 bariatric patients who underwent liver needle biopsy intra-operatively. Liver histology was compared in three tertiles of oxygen desaturation index (ODI), <6.7, 6.8–18.5, and >18.5 /h. The BMI was similar in all tertiles varying from 45.7 to 48.3 kg/m2, whereas patients with more severe OSA had higher prevalence of type 2 diabetes, dyslipidemia, and hypertension. There was a significant increase in liver steatosis, ballooning, lobular inflammation, NAS, and liver fibrosis with increased ODI. After the adjustment for type 2 diabetes, inflammation, age, and sex, the ODI remained independently associated with higher NAS and the severity of liver fibrosis. Notably, similarly to Polotsky et al. (2009), ALT and AST values were within the normal range in all patients, regardless of the severity of OSA and NASH. Thus, emerging evidence demonstrates that there is an association between the severity of hypoxic indexes in patients with OSA and the severity of NAFLD diagnosed by liver biopsy. The effect of CPAP treatment on NAFLD pathology has not been examined.

Bottom Line:
Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known.Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation.The mouse model provided insight in the pathogenesis of liver injury showing that (1) IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA) flux into the liver; (2) IH up-regulates lipid biosynthetic pathways in the liver; (3) IH induces oxidative stress in the liver; (4) IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis.

ABSTRACTObstructive sleep apnea (OSA) is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH). OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD). NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH), liver fibrosis, and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1) IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA) flux into the liver; (2) IH up-regulates lipid biosynthetic pathways in the liver; (3) IH induces oxidative stress in the liver; (4) IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done.